The present invention relates to a method for the production of 14 hydroxyl-opiates, and more particularly to a method of producing 14-hydroxyl-opiates through 1-halo-northebaine derivatives.
An example of a 14-hydroxyl-opiate is oxycodone. Oxycodone is a semi-synthetic opioid agonist that is used as an alternative to morphine in controlling severe acute postoperative or posttraumatic pain or cancer pain. Oxycodone is currently commercially produced in two steps from thebaine which is extracted from a natural source or synthetically derived from a natural product. The synthetic thebaine is made in at least three steps from hydrocodone that is generated in two steps from codeine.
In more general terms, conventional methods for producing 14-hydroxyl-opiates typically involve multi-step synthetic methods that are expensive and inefficient. Attempts to improve efficiency have included the use of transition metal oxidants such as ruthenium tetraoxide, manganese(IV)oxide, and catalytic cobalt compounds with oxygen or air on codeine or derivatives of morphine followed by reduction of the resultant 14-hydroxyl-codeinone. Overall, these oxidative methods result in low yield due in part to difficult isolations from complex mixtures of byproducts in remaining inorganic salts, and suffer from poor reproducibility.
Enzymatic methods of conversion have also been attempted, but these methods, because of the low concentrations of opiate substrate in the reaction medium and slow kinetics, are costly and difficult to scale up.
The conventional route to preparing thebaine is disclosed in the literature as follows:

Similarly, 1-bromothebaine has reportedly been synthesized from Formula 7 as follows:

There is therefore a need for an improved method of conversion that is easily scaled up and economical for manufacturing purposes.